Development of innovative therapy combining molecularly targeted drugs and immunotherapy

• Project/Area Number: 26461419
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: Toshio Kitawaki 京都大学, 医学研究科, 助教 (50378684)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ダサチニブ / 免疫チェックポイント阻害剤 / NK細胞 / サイトメガロウイルス / 免疫チェックポイント阻害薬 / 分子標的薬 / チロシンキナーゼ阻害剤 / 併用療法 / PD-1

Outline of Final Research Achievements

We found expansion of memory-like NK cells in peripheral blood of chronic myeloid leukemia and Ph-positive acute lymphoblastic leukemia patients treated with dasatinib, and revealed that cytomegalovirus reactivation plays an important role in lymphocytosis observed in these patients. Furthermore, increases in PD-1-expressing CD56-negative NK cells were noted in these patients. Cytotoxic activity of these PD-1-expressing NK cells were enhanced by PD-1 blockade with nivolumab. In a mouse model using a colon cancer cell line, CT26, combination therapy with dasatinib and anti-PD-L1 antibody did not show any synergistic effect.

Research Products

• [Journal Article] Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib (2017)
  • Author(s): Ishiyama K, Kitawaki T, Sugimoto N, Sozu T, Anzai N, Okada M, Nohgawa M, Hatanaka K, Arima N, Ishikawa T, Tabata S, Onaka T, Oka S, Nakabo Y, Amakawa R, Matsui M, Moriguchi T, Takaori-Kondo A, Kadowaki N
  • Journal Title: Leukemia Volume: 31 Issue: 1 Pages: 203-212
  • DOI: 10.1038/leu.2016.174
  • Peer Reviewed
• [Presentation] Dasatinib Expands Pre-Existing, CMV-Associated, Highly Differentiated NK Cells in Ph+ Leukemia (2014)
  • Author(s): Ken-ichi Ishiyama, Toshio Kitawaki, Akifumi Takaori and Norimitsu Kadowaki
  • Organizer: 56th American Society of Hematology
  • Place of Presentation: San Francisco, California, USA
  • Year and Date: 2014-12-07